Abstract Pseudomyxoma peritonei (PMP), an insidious but lethal malignancy, refers to peritoneal metastases from mucinous appendix neoplasms (MAN). PMP is poorly responsive to systemic chemotherapy and frequently recurs despite aggressive and morbid locoregional surgical therapy. For low-grade PMP (LG-PMP), nearly all of the deleterious clinical consequences are related to compressive organ dysfunction from excessive production and intra-abdominal accumulation of paucicellular mucus (predominantly composed of mucin 2 [MUC2] protein). Conversely, high-grade PMP (HG-PMP) is more cellular and invasive, and the abundant extracellular mucus provides a protective environment for cancer cells to thrive. We hypothesize that reducing extracellular mucus accumulation will minimize compressive organ dysfunction by decreasing the mucinous tumor burden of PMP (especially LG-PMP) and improve the efficacy of chemotherapeutic or targeted drugs by removing the protective mucus barrier surrounding neoplastic cells (especially HG-PMP). In this proposal, we will test the efficacy of combinatorial mucolytic therapy, using bromelain (BR) + N-acetylcysteine (NAC), to dissolve extracellular mucus in clinically relevant in vitro and in vivo patient-derived models of LG- and HG-MAN/PMP. Successful outcome of the proposed studies will overcome a major hurdle for treating PMP, which is the mass-effect and cytoprotective-effect of abundant extracellular mucus. In addition, our proposed research provides a novel treatment dimension for PMP that may be applied to mucinous colorectal, pancreatic and ovarian cancers. Our proposal is feasible since we are a major referral center for the management of patients with PMP, the proposed drug combination effectively dissolves mucus in-silico, and we have developed in vitro and in vivo patient-derived models of MAN/PMP that are representative of the clinical disease.